1. Field of the Invention
This invention relates to formulations of nerve growth factor (“NGF”) and their use to induce nerve cell growth, differentiation, survival, repair, maturation, or function in vivo or ex vivo. More particularly, this invention relates to such pharmaceutical compositions having increased stability and solubility characteristics for the NGF component, particularly human recombinant NGF (“rhNGF”), and those making possible the ability to create stable forms thereof for safe, effective therapeutic administration to human subjects.
2. Description of Related Disclosures
Nerve growth factor (NGF) is a neurotrophic factor required for the growth and survival of sympathetic and sensory neurons during development and in mature animals (1). Clinical indications for recombinant human NGF include peripheral sensory neuropathy and Alzheimer's disease. For example, the systemic administration of NGF has been shown to reduce the sensory neuropathy induced by administration of cisplatin and taxol to mice (2,3). In recent clinical trials, NGF has been administered to humans to improve sensory function in diabetic neuropathies (4).
NGF is currently being developed as a liquid parenteral formulation. The protein stability is complicated beyond the usual chemical and physical degradation pathways due to the dimeric structure of NGF. Protein stability can be further complicated when recombinant protein is a mixture of C-terminally clipped NGF variants. The crystal structure of murine NGF shows 3 antiparallel pairs of b-strands forming a flat surface through which the monomers dimerize (5); the dimer dissociation constant is ≦10−13 M (6, 7). The rearrangement of monomers within dimers, towards an equilibrium dimer distribution, complicates quantification of NGF dimer degradation.
There exists a need for formulations containing NGF that lead to NGF stability while being safe and effective for therapeutic administration to mammals, particularly human subjects.